Persistent Fatigue and Cognitive Impairment in Toxic Oil Syndrome: Prefrontal rTMS Four Decades After the Epidemic

Background/Objectives: Toxic oil syndrome (TOS), caused by ingestion of adulterated rapeseed oil during Spain’s 1981 epidemic, remains associated with fatigue and cognitive dysfunction more than four decades later. No disease-specific treatment is established for these sequelae. We examined whether prefrontal repetitive transcranial magnetic stimulation (rTMS) was associated with changes in fatigue impact and related neurobehavioral outcomes. Methods: In this prospective open-label pilot study, 15 TOS survivors completed 20 high-frequency rTMS sessions targeting the left dorsolateral prefrontal cortex at F3 (10 Hz, 120% of resting motor threshold, 3000 pulses/session). Assessments were performed within seven days before and after treatment. The Fatigue Impact Scale for Daily Use (D-FIS) was the primary outcome. Secondary measures included the Beck Anxiety Inventory, Beck Depression Inventory-II, Pittsburgh Sleep Quality Index, Symbol Digit Modalities Test, Addenbrooke’s Cognitive Examination-III, and Trail Making Test. Paired changes were assessed using exact Wilcoxon signed-rank tests, Hedges gz, and false-discovery-rate correction. Results: Mean D-FIS decreased from 25.7 to 17.1 points (change, −8.6; 95% confidence interval, −12.8 to −4.6; p = 0.0012; gz = −0.96), with reductions in 12 participants. Anxiety and depression scores decreased by 11.4 and 10.1 points, respectively (both q = 0.0076). Sleep quality and sleep disturbances improved after adjustment. Addenbrooke’s scores increased by 8.2 points (q = 0.0076), and Trail Making Test B completion time decreased by 76.9 s (q = 0.0185). Conclusions: Prefrontal rTMS was followed by lower fatigue impact and improvement in selected secondary outcomes. The uncontrolled design precludes causal attribution; sham-controlled evaluation is warranted.